WO2016094764A1 - Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies - Google Patents
Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies Download PDFInfo
- Publication number
- WO2016094764A1 WO2016094764A1 PCT/US2015/065181 US2015065181W WO2016094764A1 WO 2016094764 A1 WO2016094764 A1 WO 2016094764A1 US 2015065181 W US2015065181 W US 2015065181W WO 2016094764 A1 WO2016094764 A1 WO 2016094764A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptides
- peptide
- wound
- wound healing
- isolated
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 229
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 158
- 230000029663 wound healing Effects 0.000 title claims abstract description 84
- 230000017423 tissue regeneration Effects 0.000 title abstract description 4
- 102000029816 Collagenase Human genes 0.000 title description 31
- 108060005980 Collagenase Proteins 0.000 title description 31
- 229960002424 collagenase Drugs 0.000 title description 31
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 78
- 206010052428 Wound Diseases 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 210000002510 keratinocyte Anatomy 0.000 claims abstract description 18
- 210000002889 endothelial cell Anatomy 0.000 claims abstract description 13
- 229920001184 polypeptide Polymers 0.000 claims abstract description 9
- 150000001413 amino acids Chemical class 0.000 claims description 22
- 102000004169 proteins and genes Human genes 0.000 claims description 17
- 108090000623 proteins and genes Proteins 0.000 claims description 17
- 230000033115 angiogenesis Effects 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 239000003102 growth factor Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 108091005804 Peptidases Proteins 0.000 claims description 9
- 239000004365 Protease Substances 0.000 claims description 9
- 230000005012 migration Effects 0.000 claims description 9
- 238000013508 migration Methods 0.000 claims description 9
- 102000004127 Cytokines Human genes 0.000 claims description 8
- 108090000695 Cytokines Proteins 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 8
- 230000007017 scission Effects 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 230000001580 bacterial effect Effects 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000002847 Surgical Wound Diseases 0.000 claims description 2
- 230000002163 immunogen Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
- 230000000975 bioactive effect Effects 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 12
- 230000004663 cell proliferation Effects 0.000 abstract description 6
- 230000004913 activation Effects 0.000 abstract description 4
- 230000009087 cell motility Effects 0.000 abstract description 2
- 238000011069 regeneration method Methods 0.000 abstract 1
- 230000000638 stimulation Effects 0.000 abstract 1
- 210000002744 extracellular matrix Anatomy 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 15
- 238000000338 in vitro Methods 0.000 description 14
- 208000014674 injury Diseases 0.000 description 14
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 13
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 13
- 230000003511 endothelial effect Effects 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 12
- 230000006378 damage Effects 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 11
- 229940115037 santyl Drugs 0.000 description 11
- 230000035755 proliferation Effects 0.000 description 10
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 108010035532 Collagen Proteins 0.000 description 8
- 102000008186 Collagen Human genes 0.000 description 8
- 102100023354 Multimerin-1 Human genes 0.000 description 8
- 229920001436 collagen Polymers 0.000 description 8
- 102000035195 Peptidases Human genes 0.000 description 7
- 239000002250 absorbent Substances 0.000 description 7
- 230000002745 absorbent Effects 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 108010067306 Fibronectins Proteins 0.000 description 6
- 102000016359 Fibronectins Human genes 0.000 description 6
- 101000658739 Homo sapiens Tetraspanin-2 Proteins 0.000 description 6
- 102100035873 Tetraspanin-2 Human genes 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000002500 effect on skin Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 108010012891 multimerin Proteins 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 101150013977 TSN1 gene Proteins 0.000 description 5
- 230000036755 cellular response Effects 0.000 description 5
- 229960004397 cyclophosphamide Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000002950 fibroblast Anatomy 0.000 description 5
- 230000035876 healing Effects 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 239000012620 biological material Substances 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 101000993347 Gallus gallus Ciliary neurotrophic factor Proteins 0.000 description 3
- 102000002938 Thrombospondin Human genes 0.000 description 3
- 108060008245 Thrombospondin Proteins 0.000 description 3
- 108010046722 Thrombospondin 1 Proteins 0.000 description 3
- 102100036034 Thrombospondin-1 Human genes 0.000 description 3
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 3
- 230000002491 angiogenic effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004924 lung microvascular endothelial cell Anatomy 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 210000003668 pericyte Anatomy 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 238000007747 plating Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000007838 tissue remodeling Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WZUVPPKBWHMQCE-XJKSGUPXSA-N (+)-haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 239000004971 Cross linker Substances 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 206010021519 Impaired healing Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 101710130567 Multimerin-1 Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010072170 Skin wound Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 102000007000 Tenascin Human genes 0.000 description 2
- 108010008125 Tenascin Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 235000010410 calcium alginate Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000008458 response to injury Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000037314 wound repair Effects 0.000 description 2
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- RWLSBXBFZHDHHX-VIFPVBQESA-N (2s)-2-(naphthalen-2-ylamino)propanoic acid Chemical compound C1=CC=CC2=CC(N[C@@H](C)C(O)=O)=CC=C21 RWLSBXBFZHDHHX-VIFPVBQESA-N 0.000 description 1
- WTKYBFQVZPCGAO-LURJTMIESA-N (2s)-2-(pyridin-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CN=C1 WTKYBFQVZPCGAO-LURJTMIESA-N 0.000 description 1
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000008076 Angiogenic Proteins Human genes 0.000 description 1
- 108010074415 Angiogenic Proteins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 101000802895 Dendroaspis angusticeps Fasciculin-1 Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000002090 Fibronectin type III Human genes 0.000 description 1
- 108050009401 Fibronectin type III Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- JJIHLJJYMXLCOY-BYPYZUCNSA-N N-acetyl-L-serine Chemical compound CC(=O)N[C@@H](CO)C(O)=O JJIHLJJYMXLCOY-BYPYZUCNSA-N 0.000 description 1
- PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108091093037 Peptide nucleic acid Proteins 0.000 description 1
- 229920005830 Polyurethane Foam Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229940127321 Structural Macromolecules Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940003587 aquaphor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical class [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Chemical class 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008619 cell matrix interaction Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- VQODGRNSFPNSQE-CXSFZGCWSA-N dexamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-CXSFZGCWSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- -1 for example Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000017730 intein-mediated protein splicing Effects 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000029774 keratinocyte migration Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 230000001785 maturational effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000001002 morphogenetic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920006264 polyurethane film Polymers 0.000 description 1
- 239000011496 polyurethane foam Substances 0.000 description 1
- 230000026341 positive regulation of angiogenesis Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003651 pro-proliferative effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035752 proliferative phase Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108010000947 protamine zinc Chemical class 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000007388 punch biopsy Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940099261 silvadene Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000007995 vascular wound healing Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- MTZBBNMLMNBNJL-UHFFFAOYSA-N xipamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1O MTZBBNMLMNBNJL-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6489—Metalloendopeptidases (3.4.24)
- C12N9/6491—Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24007—Interstitial collagenase (3.4.24.7), i.e. matrix metalloprotease 1 or MMP1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
Definitions
- Wound healing is a complex, highly-coordinated process that begins and ends with tissue remodeling.
- the extracellular matrix and its associated growth regulatory substances play a pivotal role in dynamically and reciprocally regulating the cellular response and wound healing.
- the enzymes and structural macromolecules of the extracellular matrix cooperate with cytokines and growth factors, yielding a dynamic that orchestrates healing (1-7).
- Re- epithelialization involves the migration and proliferation of epithelial tissue, primarily keratinocytes.
- Angiogenesis is the growth of new blood vessels from pre-existing conduits, and is regulated by a panoply of soluble cytokines including growth factor polypeptides, as well as cell-cell and cell-matrix interactions.
- Chronic wounds exhibit a different healing profile from normal acute wounds in that they generally remain in an inflamed state for protracted periods of time. Non-healing wounds can most commonly be observed amongst people with diabetes, venous stasis disease, and in those patients who are immobilized.
- wound healing peptides are resistant to the degrading and compromising action of the "hostile" environment, which typifies non-healing wounds.
- Prior attempts to develop advanced protein-based wound healing therapeutics have largely failed because the wound bed's robust protease profile degrades any bioactive protein entity that is delivered.
- bioactive wound healing peptides that are resistant to protease action are highly beneficial since the peptides promote tissue remodeling, angiogenesis and epithelialization despite the elevated protease profile present within the wounds.
- activation of healing help to "re-equilibrate" the wound bed, thus potentially up-regulating protease inhibitors, down-regulating host proteases or both.
- an isolated peptide that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
- the peptide includes less than 100, 95, 90, 85, 80 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25 or 20 amino acids.
- an isolated peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, wherein the peptide does not include a full-length protein from which the peptide was derived.
- the peptide includes not more than 50, 45, 40, 35, 30, 25 or 20 contiguous amino acid residues of the protein from which the peptide was derived.
- the peptide consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
- a combinatorial peptide includes an isolated peptide disclosed herein conjugated or fused to a second peptide or polypeptide.
- a composition or article of manufacture includes one or more of the isolated peptides disclosed herein, or one or more of the combinatorial peptides disclosed herein, and a carrier or excipient.
- the carrier or excipient is a pharmaceutically acceptable carrier or excipient.
- the one or more of the isolated peptides or one or more of the combinatorial peptides include protease cleavage sites; optionally the protease cleavage sites are different in different peptides or combinatorial peptides.
- the one or more isolated peptides or one or more combinatorial peptides are anchored to a scaffold, which optionally is a bioerodible and non-immunogenic scaffold.
- methods are provided to promote wound healing in a subject in need thereof.
- the methods include administering to the subject an effective amount of one or more of the isolated peptides disclosed herein, one or more of the combinatorial peptides disclosed herein, or the composition or article of manufacture disclosed herein.
- the peptide consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
- the peptide is administered in an amount effective to enhance the rate of migration of keratinocytes or endothelial cells, or a combination of keratinocytes and endothelial cells, towards a wound edge.
- the administration of the peptide results in an increase in the re- epithelialization of the wound.
- the administration of the peptide results in an increase in angiogenesis in or near the wound.
- the peptide is administered at a wound site.
- the wound is a thermal, chronic, acute or surgical wound.
- the methods further include administering to the subject a second agent.
- the second agent is a polypeptide.
- the second agent is a growth factor, cytokine, or enzyme. In some embodiments, the second agent is a growth factor, cytokine, or enzyme.
- the second agent is a non-human collagenase.
- the non-human collagenase is bacterial collagenase.
- the subject is a mammalian subject. In some embodiments, the mammalian subject is a human.
- Figures 1A-1B show that SANTYL® collagenase API releases unique fragments from human endothelial ECM and matrices derived from human fibroblasts (shown).
- the matrices were prepared and processed as described in references 5,8-10. Samples derived from buffer insoluble and soluble ECM fractions as well as self-degraded enzymes were loaded into SDS-containing PAGE and subjected to electrophoresis. Unique protein bands present within soluble fractions of digested matrices (arrowheads) were analyzed by mass spectrometry.
- Figure 2 shows that peptides derived from human endothelial ECM stimulate proliferation of human endothelial cells.
- Human microvascular endothelial cells were plated at low density in multi-well plates and treated with 100 nM peptides every other day. At day 5 post-plating the cells were counted using a coulter counter. Cell proliferation relative to control is shown, statistical significance (p ⁇ 0.05).
- Figures 3A-3B show that peptides derived from human endothelial ECM stimulate proliferation of adult human keratinocytes in dose-dependent manner.
- Adult human keratinocytes were plated at low density in multi-well plates and treated with 10 nM peptides (Figure 3A) or 1-100 nM peptides ( Figure 3B) every other day. At day 7 post-plating the cells were counted using a coulter counter. Cell proliferation relative to control ( Figure 3A) or absolute cell number grown ( Figure 3B) are shown, statistical significance (p ⁇ 0.05).
- FIG. 4 shows that peptides derived from ECM degraded by bacterial collagenase stimulate angiogenesis in vitro.
- ECM-derived peptides were dissolved in growth factor- reduced Matrigel at 100 nM, the matrix was allowed to polymerize, human microvascular endothelial cells were plated either in control low serum containing media or media containing 100 nM peptides. Representative images of cells treated with endothelial ECM- derived peptides are shown.
- FIG. 5 shows that ECM-derived peptides stimulate epithelial wound healing in vitro.
- Adult human keratinocytes were plated into glass-bottom well plates at high density. Scratch wounds were made in the cell monolayer 24h post-plating. The peptides dissolved in keratinocyte growth media (10 nM) were applied immediately after wounding. Wound closure was monitored at 0, 1, 3 and 5 hours post- injury. Dashed line outlines the wounds. Representative images of wounds treated with TSN2 and TSN6 are shown.
- Figure 6 shows the experimental design for in vivo testing of peptides.
- Balb/c mice were pre-treated with cyclophosphamide at 150 mg/kg 3 days prior to injury and with 100 mg/kg cyclophosphamide 1 day before injury.
- Cranial cutaneous wounds were created using 4 mm punch biopsy tool and immediately covered with adherent transparent dressing
- TEGADERMTM Laboratory Animal Medicine
- Figures 7A-7L show that ECM-derived peptides stimulate cellular responses to injury in a mouse model of impaired healing. Cranial cutaneous wounds were created in
- CMC carboxymethyl cellulose
- FIG 8 shows that ECM-derived peptides stimulate wound healing in mice. Wounds were created, treated as described in Figure 6 and scored in a blind manner according to the grading described in Table 2. * indicates statistical significance of findings (p ⁇ 0.05).
- FIG. 9 shows ECM-derived peptides stimulate wound epithelialization in mice. Wounds were created and treated as described in Figure 1. Wound epithelialization was measured at day 6 post wounding. ** indicate statistical significance of findings (p ⁇ 0.05). Treatments from left to right: control; TSN6, 0.1 mg/ml; TSN6, 1 mg/ml; TSN18, 0.1 mg/ml; TSN18, 1 mg/ml; PK coUagenase.
- Wound healing is predicated upon the migration and proliferation of cells at or near the wound edge and the recruitment of new or pre-existing blood vessels to the wound site.
- wound healing peptides that stimulate keratinocyte and/or endothelial cell motility and/or proliferation.
- kits and articles of manufacture comprising one or more of the wound healing peptides.
- ECM extracellular matrices
- API active pharmaceutical ingredient
- a bacterial coUagenase isolated from a Clostridial bacterium results in the liberation of several peptides not known to be found as such in nature. These peptides are believed not formed by the treatment of ECM with a human coUagenase.
- These peptides can be isolated from digested ECM, produced in cells by expression of recombinant nucleic acids encoding the peptide(s), or synthesized using conventional peptide synthesis methods well-known in the art.
- combinatorial peptides can be generated by combining all or portions of two or more wound healing peptides. Exemplary peptides and combinatorial peptides (SEQ ID NOs: 1-19) are provided in Table 1.
- the methods, kits, and articles of manufacture provided herein can include more than one peptide, wherein at least one of the peptides is selected from SEQ ID NOs: 1-19, or peptides that comprise or consist essentially of SEQ ID NOs: 1-19.
- a wound healing peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, and the peptide comprises 100, 95, 90, 85, 80 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or fewer amino acids.
- a wound healing peptide can comprise 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 amino acids.
- a wound healing peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, and the peptide does not comprise a full-length protein from which the peptide was derived.
- the peptide comprises not more than 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 or 8 contiguous amino acid residues of the protein from which the peptide was derived.
- Certain wound healing peptides are combinatorial peptides which are combinations of peptides that include at least one of the peptides disclosed herein. Such peptides are not naturally occurring and cannot be produced by in situ cleavage. Instead, combinatorial peptides are produced by chemical synthesis or by expression of a recombinant nucleic acid that encodes the combinatorial peptide, such as a protein expression vector as described elsewhere herein.
- Non-limiting examples of combinatorial peptides include peptides that comprise one or more of SEQ ID NOs: 1-8, 11, 12, 14-17.
- peptides TSN9, TSN10, TSN13, TSN18 and TSN19 are examples of combinatorial peptides; see Table 1.
- the peptides can be linked consecutively, with the C-terminal end of one peptide linked via peptide bond to the N-terminal amino acid of another peptide.
- the peptides are linked by one or more linkers that can include one or more amino acids that are not part of the peptides linked in the combinatorial peptide.
- wound healing peptides have been demonstrated herein, using well characterized in vitro and in vivo methods and wound healing assays. The results of the assays are described herein.
- the wound healing peptides provided herein are also useful in the promotion of capillary morphogenesis and to induce endothelial cell proliferation.
- Cells types that can be affected by the wound healing peptides provided herein include keratinocytes, endothelial cells such as microvascular endothelial cells, fibroblasts and pericytes.
- the wound healing peptides provided herein also can be used in conjunction with a bio-compatible wound product.
- the wound product can be, for example, a biomaterial derived from mammalian tissue.
- the wound product can be provided in purified or unpurified form.
- the wound product can be modified by the addition of one or more compounds that act as functional crosslinkers (e.g., l-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride (EDC) or N-hydroxysulfosuccinimide (sulfo-NHS)).
- EDC l-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride
- sulfo-NHS N-hydroxysulfosuccinimide
- a commercially-available wound product e.g., OASIS® Wound Matrix, distributed by Smith & Nephew, Fort Worth, Tex.
- OASIS® Wound Matrix distributed by Smith & Nephew, Fort Worth, Tex.
- a wound healing peptide in the presence or absence of one or more functional crosslinkers.
- peptides can be engineered to possess cleavage sites so that they can be quantitatively released, unhindered or without loss of bioactivity, from the scaffold to act in a temporally and spatially specific manner.
- anchoring on a scaffold would afford release of an angiogenically-active bioactive peptide before the controlled release of a bioactive peptide that promotes epithelialization.
- blood vessel formation would be activated before epithelialization so that nutrients could be locally delivered in support of the epithelialization process by the angiogenic peptide activators preceding the epithelialization activators.
- nucleic acid molecules that encode the disclosed wound healing peptides and combinatorial peptides.
- the sequence of such nucleic acids is determined according to the standard genetic code in which one or more three-nucleotide codons encode an amino acid of the wound healing peptides or combinatorial peptides.
- kits for the treatment of wounds in a subject containing one or more wound healing peptides.
- the kit includes instructions for using the peptide to treat a wound or wounds in the subject.
- the kit includes one or more other materials that enhance wound healing.
- the kit can contain a bio-compatible wound product, a growth factor, a cytokine, or an enzyme.
- Suitable subjects include, for example, a patient with having a wound.
- the patient has diabetes.
- the subject is a burn patient.
- the wound is a chronic wound.
- a non-human (e.g., bacterial) collagenase may also be included in the kit. Articles of manufacture are also provided.
- an article of manufacture includes one or more wound healing peptides (e.g., one or more peptides including the amino acid sequence of any one or more of SEQ ID NOs: 1-19) and, optionally, one or more growth factors, cytokines, or enzymes.
- the article is suitable for use in a medical treatment of a mammalian subject.
- the article can be or include a skin or tissue equivalent.
- the article comprises one or more growth factors, cytokines, or enzymes.
- a non-human (e.g., bacterial) collagenase may also be included in or on the article.
- Suitable absorbent products are capable of absorbing a wound fluid when applied at a wound site.
- the absorbent product comprises a structure that is capable of absorbing liquid and a wound healing peptide.
- Exemplary structures include, for example, bandages, gauzes, wound or sore dressings, dermal patches and adhesive tapes.
- the term "liquid absorbent structure" refers broadly to any material applied to a wound for protection, absorbance, drainage, etc. Thus, adsorbent and absorbent materials are specifically contemplated as a solid support.
- films e.g., polyurethane films
- hydrocolloids hydrophilic colloidal particles bound to polyurethane foam
- hydrogels cross-linked polymers containing about at least 60% water
- foams hydrophilic or hydrophobic
- calcium alginates nonwoven composites of fibers from calcium alginate
- cellophane cellulose with a plasticizer
- liquid absorbent structures where one or more wound healing peptides are impregnated within or attached (covalently or otherwise) to the surface of the structure.
- Wound healing peptides described herein can be produced synthetically, or by proteolytic digestion of suitable biological materials by one or more enzymes such as collagenase.
- nucleotide sequences encoding wound healing peptides can be introduced into a protein expression vector and produced in a suitable host organism (e.g., bacteria, yeast, insect cells, etc.). Regardless of the origin or method of producing the peptides, following production, the peptides can be isolated and optionally purified.
- Peptides can be engineered to possess known wound protease cleavage sites to release a bioactive wound healing peptide or an angiogenesis-activating peptide locally with time and space control. Modified Wound Healing Peptides
- wound healing peptides can be modified as is well-known in the art.
- the wound healing peptides are modified by the addition of one or more functional groups such as phosphate, acetate, or various lipids and carbohydrates.
- Wound healing peptides can also exist as peptide derivatives.
- the term "peptide derivative" refers to compound having an imino group (-NH-), and more particularly, a peptide bond.
- Peptides may be regarded as substituted amides.
- the peptide bond shows a high degree of resonance stabilization.
- Protecting groups are those groups that prevent undesirable reactions (such as proteolysis) involving unprotected functional groups.
- the protecting group is an acyl or an amide.
- the acyl is acetate.
- another functional groups such as phosphate, acetate, or various
- the protecting group is a benzyl group. In another embodiment, the protecting group is a benzoyl group.
- the technology provided herein includes combinations of such protecting groups.
- Peptide or “polypeptide” refers to a polymer in which the monomers are alpha amino acids joined together through amide bonds. Peptides are two or often more amino acid monomers long.
- Amino acid residues in peptides are abbreviated as follows:
- Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is He or I; Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gin or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Glu or E;
- Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; and Glycine is Gly or G.
- Stereoisomers e.g., D-amino acids
- unnatural amino acids such as a,a-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for compounds of the technology provided herein.
- unconventional amino acids include: .beta.
- -alanine 1-naphthylalanine, 2-naphthylalanine, 3-pyridylalanine, 4-hydroxyproline, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, nor-leucine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).
- polypeptides can be added on for the purpose of purifying or identifying or purifying the wound healing peptides.
- Protein tags make it possible, for example, for the polypeptides to be adsorbed, with high affinity, to a matrix, and for the matrix then to be washed stringently with suitable buffers without the complex being eluted to any significant extent, and for the adsorbed complex subsequently to be eluted selectively.
- protein tags which are known to the skilled person are a (His)6 tag, a Myc tag, a FLAG tag, a haemagglutinin tag, a glutathione transferase (GST) tag, an intein having an affinity chitin-binding tag or maltose-binding protein (MBP) tag.
- GST glutathione transferase
- MBP maltose-binding protein
- biological materials include, without being limited to, growth factors, cytokines, enzymes, and ECM components.
- collagenase treatment of the sub-endothelial extracellular matrix can be used in combination with wound healing peptide treatment to accelerates endothelial migration and proliferation to a level greater than the inductive influence of collagenase treatment in the absence of wound healing peptides.
- the wound healing peptides are administered orally, topically, or by parenteral means, including subcutaneous and intramuscular injection, implantation of sustained release depots, intravenous injection, intranasal administration, and the like.
- the wound healing peptides are administered in an amount or dose that is pharmaceutically or therapeutically effective.
- a pharmaceutically or therapeutically effective dose or amount refers to a dose or amount of wound healing peptides or a composition containing wound healing peptides sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
- this dose or amount will be sufficient to stimulate or augment the epithelial and/or endothelial wound healing response and, thus, induce or potentiate wound healing.
- wound healing peptides disclosed herein are provided in a variety of
- compositions compatible with peptides can include one or more wound healing peptides, and one or more carriers or excipients.
- Wound healing peptides may be administered as a pharmaceutical composition comprising one or more wound healing peptides in combination with one or more pharmaceutically acceptable carriers or excipients.
- Such compositions may be aqueous solutions, emulsions, creams, ointments, suspensions, gels, liposomal suspensions, and the like. Suitable carriers
- excipients include water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphate, acetate, gelatin, collagen, CARBOPOL®, vegetable oils, and the like.
- PEG polyethylene glycol
- phosphate acetate
- gelatin collagen
- CARBOPOL® vegetable oils
- One may additionally include suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents, for example, BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
- Cream or ointment bases useful in formulation include lanolin, SILVADENE®, AQUAPHOR®, and the like.
- Topical formulations include aerosols, bandages and other wound dressings.
- one may incorporate or encapsulate the wound healing peptides in a suitable polymer matrix or membrane, thus providing a sustained-release delivery device suitable for implantation near the site to be treated locally.
- suitable devices for delivering or administering the compositions provided herein include indwelling catheters and devices such as the ALZET® minipump.
- Ophthalmic preparations may be formulated using commercially available vehicles such as SORBI-CARE®,
- NEODECADRON® may employ topical preparations such as that described in U.S. Pat. No. 5,124,155, incorporated herein by reference.
- “Pharmaceutically acceptable salts” refer to the non-toxic alkali metal, alkaline earth metal, and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine zinc salts, which are prepared by methods well known in the art.
- the term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds provided herein with a suitable organic or inorganic acid.
- Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate and the like.
- pharmaceutically acceptable refers to compounds and compositions which may be administered to mammals without undue toxicity.
- Exemplary pharmaceutically acceptable salts include mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
- one or more wound healing peptides may be provided in a heat stable form, such as in a powdered or encapsulated formulation for delivery and use without the need for refrigeration.
- a heat stable form such as in a powdered or encapsulated formulation for delivery and use without the need for refrigeration.
- forms include solid forms, especially as a lyophilized powder.
- Lyophilized formulations typically contain stabilizing and bulking agents, for example human serum albumin, sucrose, mannitol, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Co., Easton, PA).
- Example 1 Biochemical characterization of SANTYL® collagenase API and its extracellular matrix-derived peptide producing activities: Identification and Creation of innovative, Bioactive ECM-derived Wound Healing Peptides.
- the active pharmaceutical ingredient (API) enzyme(s) present within SANTYL® collagenase Ointment were used to produce peptides from well-defined, bio- synthesized extracellular matrices derived from living, human epidermal and dermal cell cultures in vitro.
- peptides which were produced by collagenase cleavage of synthesized endothelial or fibroblastic matrices, four peptides were "re-engineered". These re-engineered peptides are not naturally produced via collagenase-digestion; the collagenase- produced "parent" peptide(s) were re-engineered to optimize and maximize wound healing potential. These include peptides TSN9, TSN10, TSN18, TSN19, which possess amino acid sequence identity to, at least, two distinct collagenase-liberated peptides identified by mass spectrometry (see Figure 1, Table 1).
- the peptides were synthesized at Tufts University Core Facility and their biological activity evaluated in a series of tests, including (i) ability to stimulate cell-specific proliferation, (ii) activation of angiogenesis and (iii) wound healing, in vitro and in vivo.
- TSN Peptides 1-9 are derived from Human Dermal Endothelial Cell Extracellular Matrix.
- TSN Peptides 10-19 are derived from Human Dermal Fibroblast Extracellular Matrix).
- the procedure for producing extracellular matrix is from Herman and Castellot, Arteriosclerosis. 1987 Sep-Oct;7(5):463-9.
- Table 1 SANTYL® coUagenase API-produced and Extracellular Matrix-derived Peptides
- TSN12 11 aa ELADSPALEIG 12 protein N-terminal domain Combination of 11
- Example 2 SANTYL® collagenase API-produced and extracellular matrix-derived peptides significantly stimulate the cellular responses to injury in vitro. Cell Proliferation, Post-Injury Migration and Angiogenesis.
- SANTYL® collagenase API-derived bioactive wound healing peptide(s) we continue to perform a battery of pre-clinical tests and trials using the well-established models of injury and repair developed, here, at Tufts University School of Medicine and the Center for Innovations in Wound Healing Research. To these ends, we took advantage of the 2D and 3D injury/repair models developed to quantify cellular responses to injury. Outcomes of these studies have conclusively revealed that the newly-discovered peptides are able to promote cellular wound healing responses. As shown in Figure 2, several TSN peptides possess profound pro-proliferative properties when delivered to human cell cultures, including keratinocytes, endothelial cells and fibroblasts.
- FIG. 2 shows that TSN1 and TSN2, as representative examples amongst other newly-identified and synthesized ECM-derived peptides, stimulate human dermally-derived microvascular endothelial cell growth in vitro.
- TSN1 and TSN2 exceed the growth-promoting activity embodied in fibroblast growth factor 2 (FGF2), which is, perhaps, amongst the most mitogenic and angiogenesis inducer activities known.
- FGF2 fibroblast growth factor 2
- these bioactive peptides promote adult human keratinocyte proliferation in the 1-10 nM range, e.g. see Figure 3B, completely accounting for the keratinocyte growth-promoting activity present within PK SANTYL collagenase API (cf. Figure 3B, PK vs. TSN1, TSN2, TSN10). This is especially noteworthy since these peptides not only promote vascular endothelial growth but, adult human keratinocyte growth.
- patent microvascular endothelial lined “tubes” can be produced in vitro when cells are either plated upon or are embedded within growth factor-reduced Matrigel.
- ECM-derived and "re-engineered” peptides are able to stimulate wound healing angiogenesis, in addition to the microvascular endothelial growth promoting activity already demonstrated, population density matched cell numbers were plated in control or peptide-treated cultures and the angiogenic activities of the peptides quantified as a function of time in culture.
- peptide- stimulated endothelial tubes are more numerous, of greater length, having more branch points then control treated endothelial cell cultures.
- TSN2 which has angiogenesis-inducing activity also promotes keratinocyte migration in response to injury
- these data suggest that the migration-enhancing activity embodied in this thrombospondin-1 domain may act upon keratinocytes and endothelial cells in the same manner or through the same molecular mechanism(s).
- Example 3 SANTYL® collagenase API-produced and extracellular matrix-derived peptides significantly stimulate the cellular responses to injury and wound healing in vivo.
- the peptides described herein which have significant migration-enhancing, growth- promoting and angiogenesis-inducing activity in vitro, similarly possess wound healing activity in vivo.
- wound healing studies in vivo a model of impaired healing, cyclophosphamide-induced neutropenia, was used.
- Full thickness excisional wounding of the cutaneous tissues located over the cranium was performed. While only one 8mm diameter full thickness excisional wound can be made per mouse, the means by which healing occurs is closely aligned with human cutaneous wound healing, i.e., via migration and proliferation vs. contraction (as is the case on the rodents' flanks).
- animals were treated according to NIH guidelines for the care and well-being of laboratory animals, were injured under full anesthesia and then receive pain-alleviation, post-operatively.
- test entities were coded so that the nature of the experiment was blinded to the investigator; and, each specimen was evaluated and scored blindly according to the wound healing system shown in Table 2, prior to unmasking the experimental code.
- Table 2 modified wound scoring system. Tissues were collected as described herein and depicted in Figure 6, sectioned and stained with Haematoxylin and eosin. Scores were assigned to each wound by an investigator in a blind manner.
- peptide-treated groups (and, in particular those treated with TSN6, which is comprised of a coiled domain contained within multimerin), were markedly stimulated to heal wounds compared to untreated controls or groups treated with collagenase, alone, or other peptides.
- Newcomb PM Herman IM. Pericyte growth and contractile phenotype: modulation by endothelial- synthesized matrix and comparison with aortic smooth muscle. J Cell Physiol. 1993 May;155(2):385-93. PMID: 8482730.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017531329A JP2018502566A (ja) | 2014-12-12 | 2015-12-11 | コラゲナーゼ由来ペプチドは組織再生および創傷治癒を促進する。 |
US15/534,140 US10485846B2 (en) | 2014-12-12 | 2015-12-11 | Collagenase-derived peptides promote tissue regeneration and wound healing |
EP15868322.7A EP3229821B1 (fr) | 2014-12-12 | 2015-12-11 | Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies |
AU2015360399A AU2015360399A1 (en) | 2014-12-12 | 2015-12-11 | Collagenase-derived peptides promote tissue regeneration and wound healing |
CA3007181A CA3007181C (fr) | 2014-12-12 | 2015-12-11 | Les peptides derives de la collagenase activent la regeneration tissulaire et la cicatrisation des plaies |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462091444P | 2014-12-12 | 2014-12-12 | |
US62/091,444 | 2014-12-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016094764A1 true WO2016094764A1 (fr) | 2016-06-16 |
Family
ID=56108243
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/065181 WO2016094764A1 (fr) | 2014-12-12 | 2015-12-11 | Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies |
Country Status (6)
Country | Link |
---|---|
US (1) | US10485846B2 (fr) |
EP (1) | EP3229821B1 (fr) |
JP (1) | JP2018502566A (fr) |
AU (1) | AU2015360399A1 (fr) |
CA (2) | CA3007181C (fr) |
WO (1) | WO2016094764A1 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023205665A2 (fr) * | 2022-04-19 | 2023-10-26 | Trustees Of Tufts College | Peptides pour favoriser la néogenèse du follicule pileux, et prévenir/atténuer les effets indésirables d'un traitement par rayonnement |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5124155A (en) | 1988-06-21 | 1992-06-23 | Chiron Ophthalmics, Inc. | Fibronectin wound-healing dressings |
WO1992013887A1 (fr) * | 1991-02-07 | 1992-08-20 | The Victoria University Of Manchester | Nouveaux peptides d'adhesion cellulaire |
US20060051774A1 (en) * | 2004-01-27 | 2006-03-09 | Dvir Dahary | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer |
US20120087862A1 (en) * | 2006-08-09 | 2012-04-12 | Homestead Clinical Corporation | Organ-specific proteins and methods of their use |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070219125A1 (en) * | 1999-11-17 | 2007-09-20 | Cojocaru Gad S | Novel thrombospondin-1 polynucleotides encoding variant thrombospondin-1 polypeptides and methods using same |
WO2001088122A2 (fr) * | 2000-05-16 | 2001-11-22 | Glaxo Group Limited | Modulation |
-
2015
- 2015-12-11 US US15/534,140 patent/US10485846B2/en active Active
- 2015-12-11 EP EP15868322.7A patent/EP3229821B1/fr active Active
- 2015-12-11 CA CA3007181A patent/CA3007181C/fr active Active
- 2015-12-11 WO PCT/US2015/065181 patent/WO2016094764A1/fr active Application Filing
- 2015-12-11 CA CA3237043A patent/CA3237043A1/fr active Pending
- 2015-12-11 AU AU2015360399A patent/AU2015360399A1/en not_active Abandoned
- 2015-12-11 JP JP2017531329A patent/JP2018502566A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5124155A (en) | 1988-06-21 | 1992-06-23 | Chiron Ophthalmics, Inc. | Fibronectin wound-healing dressings |
WO1992013887A1 (fr) * | 1991-02-07 | 1992-08-20 | The Victoria University Of Manchester | Nouveaux peptides d'adhesion cellulaire |
US20060051774A1 (en) * | 2004-01-27 | 2006-03-09 | Dvir Dahary | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer |
US20120087862A1 (en) * | 2006-08-09 | 2012-04-12 | Homestead Clinical Corporation | Organ-specific proteins and methods of their use |
Non-Patent Citations (12)
Title |
---|
AMBILY ET AL.: "The role of plasma membrane STIM1 and Ca2 +entry in platelet aggregation. STIM1 binds to novel proteins in human platelets", CELLULAR SIGNALLING, vol. 26, no. Iss. 3, 1 March 2014 (2014-03-01), pages 502 - 511, XP055454509 * |
DEMIDOVA-RICE TGEEVARGHESE AHERMAN IM: "Bioactive peptides derived from vascular endothelial cell extracellular matrices promote microvascular morphogenesis and wound healing in vitro", WOUND REPAIR REGEN, vol. 19, no. 1, January 2011 (2011-01-01), pages 59 - 70, XP055467839, DOI: 10.1111/j.1524-475X.2010.00642.x |
DEMIDOVA-RICE TNHAMBLIN MRHERMAN IM: "Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care", ADV SKIN WOUND CARE, vol. 25, 2012, pages 304 - 14 |
DEMIDOVA-RICE TNHAMBLIN MRHERMAN IM: "Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery", ADV SKIN WOUND CARE, vol. 25, August 2012 (2012-08-01), pages 349 - 70 |
DEMIDOVA-RICE TNWOLF LDECKENBACK JHAMBLIN MRHERMAN, IM: "Human platelet-rich plasma- and extracellular matrix-derived peptides promote impaired cutaneous wound healing in vivo", PLOS ONE, vol. 7, 2012, pages e32146, XP055467845, DOI: 10.1371/journal.pone.0032146 |
DULMOVITS BMHERMAN IM: "Microvascular remodeling and wound healing: A role for pericytes", INT J BIOCHEM CELL BIOL, vol. 44, 2012, pages 1800 - 12, XP028940059, DOI: 10.1016/j.biocel.2012.06.031 |
FALANGA V.: "Wound healing and its impairment in the diabetic foot", LANCET, vol. 366, 2005, pages 1736 - 1743, XP025277278, DOI: 10.1016/S0140-6736(05)67700-8 |
HERMAN IM: "Endothelial cell matrices modulate smooth muscle cell growth, contractile phenotype and sensitivity to heparin", HAEMOSTASIS, vol. 20, no. 1, 1990, pages 166 - 77 |
HERMAN IMCASTELLOT JJ JR: "Regulation of vascular smooth muscle cell growth by endothelial-synthesized extracellular matrices", ARTERIOSCLEROSIS, vol. 7, no. 5, September 1987 (1987-09-01), pages 463 - 9 |
NEWCOMB PMHERMAN IM: "Pericyte growth and contractile phenotype: modulation by endothelial-synthesized matrix and comparison with aortic smooth muscle", J CELL PHYSIOL., vol. 155, no. 2, May 1993 (1993-05-01), pages 385 - 93 |
POSTLETHWAITE ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE, vol. 75, 1978, pages 871 - 875 |
SCHULTZ GSDAVIDSON JKIRSNER RBORNSTEIN PHERMAN IM, DYNAMIC RECIPROCITY IN THE WOUND MICROENVIRONMENT. WOUND REPAIR REGEN, vol. 19, no. 2, March 2011 (2011-03-01), pages 134 - 48 |
Also Published As
Publication number | Publication date |
---|---|
EP3229821B1 (fr) | 2020-09-23 |
EP3229821A4 (fr) | 2018-06-13 |
EP3229821A1 (fr) | 2017-10-18 |
AU2015360399A1 (en) | 2017-08-03 |
JP2018502566A (ja) | 2018-02-01 |
US10485846B2 (en) | 2019-11-26 |
CA3237043A1 (fr) | 2016-06-16 |
US20180339013A1 (en) | 2018-11-29 |
CA3007181A1 (fr) | 2016-06-16 |
CA3007181C (fr) | 2024-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20090111738A1 (en) | Fibronectin polypeptides and methods of use | |
US6331409B1 (en) | Methods and compositions for wound healing | |
EP2409988A2 (fr) | Fragments de peptides pour induire la synthèse de protéines de matrice extracellulaire | |
EP2938626A1 (fr) | Hydrogels peptidiques ultracourts auto-assemblés pour cicatrisation de plaies, soins de la peau et applications cosmétiques | |
KR102254260B1 (ko) | 다양한 피부 병태의 치료에 유용한 인간 c-x-c 케모카인으로부터 유래된 테트라펩타이드 | |
US10463745B2 (en) | Materials for tissue regeneration | |
CN103097405B (zh) | 用于伤口愈合的新型肽 | |
US6025150A (en) | Methods and compositions for wound healing | |
RU2458069C2 (ru) | Выделенный пептид для усиления ранозаживляющей активности кератиноцитов, композиция для заживления ран у млекопитающего и лекарственное средство для применения при заживлении ран у млекопитающего | |
EP3229821B1 (fr) | Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies | |
AU2013214039B2 (en) | Bifunctional peptide | |
CN106488773B (zh) | Apc类似物用于创伤愈合的用途 | |
US8663617B2 (en) | Wound healing peptides and methods of use thereof | |
US8288334B2 (en) | Peptides for wound healing | |
EP2395015B1 (fr) | Peptides utilisés dans la cicatrisation des blessures | |
WO2018071709A1 (fr) | Peptides dérivés de la fibronectine présentant une bioactivité améliorée et une sensibilité réduite à la dégradation de l'élastase des neutrophiles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15868322 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017531329 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2015868322 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2015360399 Country of ref document: AU Date of ref document: 20151211 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 3007181 Country of ref document: CA |